Tissue-treatment methods

ABSTRACT

Polymer insulators and methods of using polymer insulators are disclosed. In some embodiments, a method includes separating a first portion of a subject&#39;s tissue from a second portion of the subject&#39;s tissue so that there is a space between the first and second portions of tissue. Deionized water, a buffered saline solution, liquid polymers, gels, particles, foams, and/or gases are disposed between the first and second portions of tissue, and the first portion of tissue is exposed to energy to treat the first portion of tissue.

TECHNICAL FIELD

This invention relates to tissue-treatment methods.

BACKGROUND

Energy, such as RF energy, can be employed to degrade unhealthy orunwanted tissue, such as a wart, a mole, a cyst, scar tissue, and/or atumor. In some cases, for example, an RF probe can be delivered into theunhealthy or unwanted tissue via a catheter. Once positioned within thetumor, RF-emitting tines can be deployed and activated. Upon activation,the tines can emit RF energy to degrade the tissue by, for example,heating the tissue.

SUMMARY

The invention relates to polymer insulators and methods of using thesame.

In one aspect, the invention features a method that includes separatinga first portion of tissue of a subject from a second portion of tissueof the subject so that there is a space between the first and secondportions of tissue. The method also includes disposing a materialbetween the first and second portions of tissue, and exposing the firstportion of tissue to energy to treat the first portion of tissue. Thematerial disposed between the first and second portions of tissue can beone or more of the following: deionized water; a buffered salinesolution; liquid polymers; gels; particles; foams; and/or gases.

In another aspect, the invention features a method that includesdisposing a material between a first portion of tissue of a subject anda second portion of tissue of the subject. The method also includesexposing the first portion of tissue to energy to treat the firstportion of tissue. The second portion of tissue can be substantiallyunexposed to the energy while the first portion of tissue is exposed tothe energy. The distance between the first and second portions of tissueis at most about five centimeters, and the material disposed between thefirst and second portions of tissue can be one or more of the following:deionized water; a buffered saline solution; liquid polymers; gels;particles; foams; and/or gases.

The methods can include one or more of the following features.

In some embodiments, the second portion of tissue is substantiallyunexposed to the energy while the first portion of tissue is exposed tothe energy.

In certain embodiments, the energy includes RF energy, microwave energy,ultrasonic energy, laser energy, and/or heat. In some embodiments,exposing the first portion of tissue to energy includes cooling thefirst portion of tissue.

In some embodiments, the first portion of tissue includes unhealthytissue (e.g., cancerous tissue), and/or the second portion of tissueincludes healthy tissue. Examples of tissue include bodily vesseltissue, bladder tissue, bone tissue, brain tissue, breast tissue,bronchi tissue, diaphragm tissue, esophagus tissue, gall bladder tissue,heart tissue, intestine tissue, kidney tissue, larynx tissue, livertissue, lung tissue, lymph vessel tissue, lymph node tissue, nervetissue, ovary tissue, pancreas tissue, prostate tissue, skin tissue,stomach tissue, and thyroid tissue, trachea tissue, urethra tissue,ureter tissue, uterus tissue, and vertebral disc tissue.

In certain embodiments, the material is formed of particles. Theparticles can have, for example, a size of at most about 10,000 microns.The particles can include one or more polymeric materials. The particlescan include a material having a dielectric constant of at least about2.1 and/or a dielectric strength of at least about 100 Kv/mm in someembodiments.

In some embodiments, the material is a liquid polymer.

In certain embodiments, the material is a foam.

In some embodiments, the material is a gas. Examples of gases includeair, helium, neon, argon, krypton, xenon, nitrogen, and carbon dioxide.

In some embodiments, the material is deionized water and/or a bufferedsaline solution.

In certain embodiments, the material is a water soluble polysaccharideand/or an ionically cross-linkable polymer.

In certain embodiments, the material is a ceramic material.

In some embodiments, the material is capable of undergoing anendothermic reaction.

In some embodiments, the space between the first and second portions oftissue is at most about five centimeters.

The methods can provide one or more of the following advantages.

In some embodiments, the methods can protect healthy or desired tissuefrom damage, while treating (e.g., ablating, degrading, destroying)unhealthy or undesired tissue.

In certain embodiments, the methods can allow relatively small regionsof desired or healthy tissue to be protected while treating (e.g.,ablating, degrading, destroying) undesired or unhealthy tissue.

In certain embodiments, the methods can protect regions of desired orhealthy tissue that are difficult to access.

Features and advantages are in the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a cross-sectional view of a cancerous liver of a subject.

FIG. 1B is a cross-sectional view of the liver of FIG. 1A with aprotective layer of particles disposed between the cancerous andnon-cancerous tissue regions.

FIG. 1C illustrates administration of particles between cancerous andnon-cancerous tissue regions of the liver of FIG. 1A.

FIG. 1D illustrates emission of energy within the cancerous tissueregion of the liver of FIGS. 1A, 1B, and 1C to degrade the canceroustissue.

Like reference symbols in the drawings indicate like elements.

DETAILED DESCRIPTION

The methods include disposing one or more materials between a region ofunhealthy tissue and a region of healthy tissue, and exposing theunhealthy tissue to energy (e.g., RF energy) to damage or destroy theunhealthy tissue. The materials can include one or more of thefollowing: deionized water; a buffered saline solution; liquid polymers;gels; particles; foams; and/or gases. The material disposed between theunhealthy and healthy tissue regions can protect the healthy tissue sothat it is substantially unharmed by the energy.

For example, FIG. 1A shows a portion 100 of a subject including a liver110 and skin 120. Liver 110 includes healthy tissue 130 and unhealthytissue 140 (e.g., a cancerous tissue, such as a cancerous tumor).

FIG. 1B shows healthy tissue 130 separated from unhealthy tissue 140 bya protective layer 145 of particles 150. As discussed in more detailbelow, particles 150 can protect healthy tissue 130 while unhealthytissue 140 is treated with energy.

For example, particles 150 can be formed of a material that is a poorconductor of certain types of energy (e.g., RF energy) relative totissues 130 and 140 of the subject. Thus, when inserted between healthyand unhealthy tissues 130, 140, particles 150 substantially preventenergy applied to unhealthy tissue 140 from harming healthy tissue 130.As a result, healthy tissue 130 is substantially protected from harmwhen energy is applied to unhealthy tissue 140.

In some embodiments, particles 150 are at least partially formed fromone or more polymers. Examples of polymers include polyvinyl alcohols,polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,carboxymethyl celluloses, hydroxyethyl celluloses, substitutedcelluloses, polyacrylamides, polyethylene glycols, polyamides,polyureas, polyurethanes, polyesters, polyethers, polystyrenes,polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids),polypropylene, polytetrafluorethylene, polyethyleneterephthalate,polycarbonate, polyphenyleneoxide, polysulfone, polyhydantoine,polyamide-imide, polyimide, cellulose triacetate, cellulose acetatebutyrate, and copolymers or mixtures thereof.

Additional examples of materials from which particles 150 can be atleast partially formed include alginates (e.g., sodium alginate),alginate salts, xanthan gums, natural gum, agar, agarose, chitosan,carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gumarabic, gum ghatti, gum karaya, gum tragacanth, hyalauronic acid, locustbeam gum, arabinogalactan, pectin, amylopectin, other water solublepolysaccharides and other ionically cross-linkable polymers.

In some embodiments, particles 150 are at least partially formed of abio-absorbable and/or bio-erodible material, such as a polysaccharide(such as an alginate); a polysaccharide derivative; a water solublepolymer (such as a polyvinyl alcohol, e.g., that has not beencross-linked); biodegradable poly DL-lactide-poly ethylene glycol(PELA); a hydrogel (e.g., polyacrylic acid, haluronic acid, gelatin,carboxymethyl cellulose); a polyethylene glycol (PEG); chitosan; apolyester (e.g., a polycaprolactone); a poly(lactic-acid) (PLA); apoly(lactic-co-glycolic) acid (e.g., a poly(d-lactic-co-glycolic) acid);or a combination thereof.

In certain embodiments, particles 150 are at least partially formed ofone or more ceramic materials. In general, a ceramic material containsone or more metallic elements and one or more non-metallic elements.Examples of ceramics include metal oxides, such as aluminum oxide,cerium oxide, copper oxide, iron oxide, magnesium oxide, and potassiumoxide.

In some embodiments, particles 150 can be formed of a glass. Examples ofglasses include oxides of silicon, beryllium, boron, germanium,phosphorous, vanadium, lead, tin, zinc, zirconium, and titanium, as wellas such nonoxide compounds as germanium sulphide, metal fluorides, andiodites. Other examples of glasses include certain metallic selenides,tellurides, arsenides, phosphides, and obsidian.

In certain embodiments, particles 150 contain encapsulated air (e.g., toenhance the protective ability of particles 150). In some embodiments,particles 150 contain an encapsulated composition capable of undergoingan endothermic reaction. For example, particles 150 can encapsulate aammonium nitrate and water composition. Consequently, particles 150 canabsorb greater amounts of energy (e.g., heat) in some cases.

In some embodiments, particles 150 are formed from a material that has arelatively high dielectric constant. For example, particles 150 can havea dielectric constant that is higher than the dielectric constant oftissues 130 and 140. This can, for example, allow protective layer 145to be a relatively poor conductor of RF energy. For example, particles150 can be formed of a material having a dielectric constant of at leastabout 2.0 (e.g., at least about 2.1, at least about 2.7, at least about3.1). In some embodiments, particles 150 can be formed of a materialhaving a dielectric constant of from about 2.0 to about 4.5 (e.g., fromabout 2.1 to about 4.5, from about 2.7 to about 4.5, from about 3.1 toabout 4.5). The term dielectric constant, as used herein, is measured byASTM D150 at 50 Hz and 20° C.

In some embodiments, the material from which particles 150 are made hasa relatively high dielectric strength. For example, particles 150 canhave a dielectric strength that is higher than the dielectric strengthof tissues 130 and 140. This can, for example, allow layer 145 to be arelatively poor conductor of RF energy. For example, particles 150 canbe formed of a material having a dielectric strength of at least about100 kV/mm (e.g., at least about 200 kV/mm, at least about 240 kV/mm, atleast about 280 kV/mm). In some embodiments, particles 150 can be formedof a material having a dielectric strength of from about 50 kV/mm toabout 350 kV/mm (e.g., from about 100 kV/mm to about 300 kV/mm, fromabout 200 kV/mm to about 300 kV/mm, from about 240 kV/mm to about 300kV/mm, from about 280 kV/mm to about 300 kV/mm). The term dielectricstrength, as used herein, is measured by ASTM D149.

In certain embodiments, particles 150 can be formed of a material havinga relatively high dissipation factor. For example, particles 150 canhave a dissipation factor that is higher than the dissipation factor oftissues 130 and 140. This can, for example, allow layer 145 to be arelatively poor conductor of RF energy. For example, particles 150 canbe formed of a material having a dissipation factor of at least about0.2 (e.g., at least about 0.7, at least about 1.5, at least about nine,at least about 21). The term dissipation factor, as used herein, ismeasured by ASTM D150 at 50 Hz and 20° C.

In some embodiments, particles 150 can be formed of a material having arelatively high volume resistivity. For example, particles 150 can havea volume resistivity that is higher than the volume resistivity oftissues 130 and 140. This can, for example, allow layer 145 to be arelatively poor conductor of RF energy. For example, particles 150 canbe formed of a material having a volume resistivity of at least about10⁶ to about 10¹⁷ ohm-cm (e.g., at least about 10¹⁴ ohm-cm, at leastabout 10¹⁶ ohm-cm, at least about 10¹⁷ ohm-cm). As used herein, thevolume resistivity of a particle is measured by ASTM D257-99.

In certain embodiments, particles 150 can be formed of a material havinga relatively low surface resistivity. For example, particles 150 canhave a surface resistivity that is lower than the surface resisitivityof tissues 130 and 140. For example, particles 150 can be formed of amaterial having a surface resistivity of at most about 10¹² to about10¹⁶ ohm-cm (e.g., at most about 10¹⁶ ohm-cm, at most about 10¹⁴ ohm-cm,at most about 10¹² ohm-cm). The term surface resistivity, as usedherein, is measured by ASTM D257-99.

In certain embodiments, the material from which particles 150 are madecan be chosen based on the intensity and/or type of energy used to treatunhealthy tissue 140. As an example, in embodiments in which RF energyand/or microwave energy is used, it can be beneficial to use particlesformed of a material with a higher dielectric constant and/or a higherdielectric strength. As an additional example, in embodiments in whichultrasonic energy is used, it can be beneficial to use particles formedof a material that can retard the transmission of ultrasonic energytherethrough. As another example, in embodiments in which laser energyis used, it can be beneficial to use particles formed of a material thatis capable of absorbing and/or refracting laser energy.

In some embodiments, particles 150 have a diameter of no greater thanabout 10,000 microns (e.g., no greater than about 7,500 microns, nogreater than about 5,000 microns, no greater than about 2,500 microns,no greater than about 2,000 microns, no greater than about 1,5000microns, no greater than about 1,000 microns, no greater than about 500microns, no greater than about 400 microns, no greater than about 300microns, no greater than about 200 microns, no greater than about 100microns). In some embodiments, particles 150 have a diameter of about100 microns to about 10,000 microns (e.g., about 100 microns to about1000 microns, about 100 microns to 500 microns, about 2,500 microns toabout 5,000 microns, about 5,000 microns to about 10,000 microns, about7,500 microns to about 10,000 microns).

FIG. 1C shows a method of disposing particles 150 between healthy tissue130 and unhealthy tissue 140 using a needle 160. Needle 160 is in fluidcommunication with a syringe 170, which contains particles 150 suspendedin a carrier fluid 180. An end 190 of needle 160 is inserted throughskin 120 of the subject and into healthy tissue 130. Needle 160 isinserted until end 190 is positioned between healthy and unhealthytissues 130, 140 in order to separate healthy tissue 130 from unhealthytissue 140 and form a gap between healthy and unhealthy tissues 130,140. Particles 150 and carrier fluid 180 are then injected from syringe170 into the gap to form protective layer 145. In some embodiments, thisprocess is repeated until protective layer 145 reaches a desiredthickness. In certain embodiments, the method is performed so thatprotective layer 145 covers only a particular region or regions ofunhealthy tissue 140. For example, any of various imaging modalities,such as ultrasound, CT, MRI, and/or fluoroscopy, can be used to help theuser (e.g., a physician) to position needle 160 in a targeted region ofthe tissue. Consequently, particles 150 can be disposed (e.g., injected)substantially only in the targeted region. It may be unnecessary, forexample, to completely separate healthy tissue 130 from unhealthy tissue140 when only a particular region of healthy tissue 130 is exposed toenergy emitted during a treatment. In such cases, particles 150 can berestricted to regions likely to be exposed to the energy.

Carrier fluid 180 can be a pharmaceutically acceptable carrier, such asa buffered saline solution, non-ionic contrast agent, therapeutic agent,or a combination of these carriers. In some embodiments, carrier fluid180 includes deionized water, water for injection, liquid polymer, gelpolymer, gas, or a combination of these carriers. Carrier fluid 180, insome cases, can contribute to the protection of healthy tissue 130. Incertain embodiments, carrier fluid 180 includes one or more insulatingmaterials, such as glass fibers. The insulating materials can enhancethe ability of carrier fluid 180 to contribute to the protection ofhealthy tissue 130.

In some embodiments, particles 150 are not suspended in a carrier fluid.For example, particles 150 alone can be contained within syringe 170,and injected from syringe 170 into the gap between healthy tissue 130and unhealthy tissue 140.

While embodiments have been described in which a needle is used to formthe opening between healthy tissue 130 and unhealthy tissue 140, in someembodiments, other techniques can be used to form this opening. Forexample, the opening can be formed using an open procedure in which anincision is made in the subject to gain access to unhealthy tissue 140.As another example, blunt dissection techniques may be used to form theopening between healthy tissue 130 and unhealthy tissue 140. Afterforming the opening, healthy tissue 130 can be separated from unhealthytissue 140 using any of various techniques. For example, a needle can beinjected between healthy and unhealthy tissues 130, 140. As anotherexample, one or more gases or liquids can be pumped into the regionbetween healthy tissue 130 and unhealthy tissue 140. After separatinghealthy tissue 130 from unhealthy tissue 140, particles 150 can beimplanted within a gap created between the separated healthy andunhealthy tissues 130, 140 using any of various techniques. For example,in some embodiments, particles 150 can be injected into the gap via aneedle, directly from a syringe, or a catheter.

FIG. 1D illustrates a method of treating unhealthy tissue 140 with RFenergy using an RF probe 185 (e.g., a 3.5 centimeter coaxial LeVeenelectrode, available from Boston Scientific Corporation). Probe 185 ispositioned within unhealthy tissue 140 (e.g., by insertion through skin120 of the subject). Once positioned within unhealthy tissue 140, tines195 of RF probe 185 are deployed within unhealthy tissue 140, and RFprobe 185 is activated so that RF energy is emitted from tines 195. TheRF energy emitted from tines 195 can heat unhealthy tissue 140 aroundtines 195 to treat (e.g., ablate, damage destroy) portions of unhealthytissue 140 that are exposed to the energy.

Protective layer 145 substantially prevents the RF energy frompenetrating healthy tissue 130 when unhealthy tissue 140 is exposed tothe RF energy. For example, the RF energy is prevented from penetratinghealthy tissue 130 with a substantially harmful intensity. Thus, themethod can be used to treat unhealthy tissue 140 without substantiallyharming healthy tissue 130.

The level of protection provided by protective layer 145 of particles150 can be a function of the thickness of protective layer 145. As anexample, in some embodiments, as the thickness of protective layer 145increases, its ability to conduct energy (e.g., heat and/or RF energy)can decrease, and, as the thickness of protective layer 145 decreases,its ability to conduct energy (e.g., heat and/or RF energy) candecrease. In such embodiments, it can become more difficult for energyto be transported from unhealthy tissue 140 to healthy tissue 130 viaprotective layer 145 as the thickness of protective layer 145 increases,and it can become easier for energy to be transported from unhealthytissue 140 to healthy tissue 130 via protective layer 145 as thethickness of protective layer 145 decreases. Thus, it may be beneficialto increase the thickness of protective layer 145 as the intensity ofthe energy used to treat unhealthy tissue 140 increases, and to decreasethe thickness of protective layer 145 as the intensity of energydecreases (e.g., to obtain a desired degree of insulation while keepingthe space between unhealthy tissue 140 and healthy tissue 130 relativelysmall to decrease possible trauma to the subject).

The thickness of protective layer 145 can be modified using any ofvarious techniques. For example, the thickness of protective layer 145can be increased or decreased by increasing or decreasing the size ofparticles 150, and/or by disposing a greater or lesser number ofparticles across a thickness of the gap between healthy and unhealthytissues 130, 140. In certain embodiments, multiple layers of particles150 are disposed between healthy tissue 130 and unhealthy tissue 140 inorder to increase the thickness of protective layer 145.

In some embodiments, after separating healthy tissue 130 from unhealthytissue 140, the gap between healthy and unhealthy tissues 130, 140 canbe at most about five centimeters (e.g., at most about four centimeters,at most about three centimeters, at most about two centimeters, at mostabout one centimeter, at most about 0.5 centimeter, at most about 0.25centimeter, or at most about 0.1 centimeter). For example, protectivelayer 145 of particles 150 can have a thickness of at most about fivecentimeters (e.g., at most about four centimeters, at most about threecentimeters, at most about two centimeters, at most about onecentimeter, at most about 0.5 centimeter, at most about 0.25 centimeter,or at most about 0.1 centimeter). In some embodiments the gap betweenhealthy and unhealthy tissues 130, 140 can be about 0.1 centimeter toabout five centimeters (e.g., about 0.1 centimeter to about threecentimeters, about 0.1 centimeter to about one centimeter, about 0.1centimeter to about 0.5 centimeter, about 0.1 centimeter to about 0.25centimeter). For example, protective layer 145 of particles 150 can havea thickness of about 0.1 centimeter to about five centimeters (e.g.,about 0.1 centimeter to about three centimeters, about 0.1 centimeter toabout one centimeter, about 0.1 centimeter to about 0.5 centimeter,about 0.1 centimeter to about 0.25 centimeter).

In certain embodiments, particles 150 include one or more therapeuticagents (e.g., drugs) that can be delivered to healthy and/or unhealthytissues 130, 140. The therapeutic agent(s) can be in and/or on theparticle. Therapeutic agents include agents that are negatively charged,positively charged, amphoteric, or neutral. Therapeutic agents includegenetic therapeutic agents, non-genetic therapeutic agents, and cells,and can be negatively charged, positively charged, amphoteric, orneutral. Therapeutic agents can be, for example, materials that arebiologically active to treat physiological conditions; pharmaceuticallyactive compounds; gene therapies; nucleic acids with and without carriervectors; oligonucleotides; gene/vector systems; DNA chimeras; compactingagents (e.g., DNA compacting agents); viruses; polymers; hyaluronicacid; proteins (e.g., enzymes such as ribozymes); immunologic species;nonsteroidal anti-inflammatory medications; oral contraceptives;progestins; gonadotrophin-releasing hormone agonists; chemotherapeuticagents; and radioactive species (e.g., radioisotopes, radioactivemolecules). Non-limiting examples of therapeutic agents includeanti-thrombogenic agents; antioxidants; angiogenic and anti-angiogenicagents and factors; anti-proliferative agents (e.g., agents capable ofblocking smooth muscle cell proliferation); calcium entry blockers; andsurvival genes which protect against cell death.

Exemplary non-genetic therapeutic agents include: anti-thrombotic agentssuch as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline arginine chloromethylketone);anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, cisplatin, doxorubicin; vinblastine, vincristine,epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodiescapable of blocking smooth muscle cell proliferation, and thymidinekinase inhibitors; anesthetic agents such as lidocaine, bupivacaine andropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone,an RGD peptide-containing compound, heparin, hirudin, antithrombincompounds, platelet receptor antagonists, anti-thrombin antibodies,anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors,platelet inhibitors and tick antiplatelet peptides; vascular cell growthpromoters such as growth factors, transcriptional activators, andtranslational promoters; vascular cell growth inhibitors such as growthfactor inhibitors, growth factor receptor antagonists, transcriptionalrepressors, translational repressors, replication inhibitors, inhibitoryantibodies, antibodies directed against growth factors, bifunctionalmolecules consisting of a growth factor and a cytotoxin, bifunctionalmolecules consisting of an antibody and a cytotoxin; protein kinase andtyrosine kinase inhibitors (e.g., tyrphostins, genistein, quinoxalines);prostacyclin analogs; cholesterol-lowering agents; angiopoietins;antimicrobial agents such as triclosan, cephalosporins, aminoglycosidesand nitrofurantoin; cytotoxic agents, cytostatic agents and cellproliferation affectors; vasodilating agents; and agents that interferewith endogenous vasoactive mechanisms.

Exemplary genetic therapeutic agents include: anti-sense DNA and RNA;DNA coding for: anti-sense RNA, tRNA or rRNA to replace defective ordeficient endogenous molecules, angiogenic factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, epidermal growth factor, transforming growthfactor α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor a, hepatocytegrowth factor and insulin like growth factor, cell cycle inhibitorsincluding CD inhibitors, thymidine kinase (“TK”) and other agents usefulfor interfering with cell proliferation, and the family of bonemorphogenic proteins (“BMP's”), including BMP2, BMP3, BMP4, BMP5, BMP6(Vgr1), BMP7 (OP1), BMP8, BMP9, BMP10, BM11, BMP12, BMP13, BMP14, BMP15,and BMP16. Currently preferred BMP's are any of BMP2, BMP3, BMP4, BMP5,BMP6 and BMP7. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively or, in addition, molecules capable of inducingan upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem.

Vectors of interest for delivery of genetic therapeutic agents include:Plasmids, Viral vectors such as adenovirus (AV), adenoassociated virus(AAV) and lentivirus, Non-viral vectors such as lipids, liposomes andcationic lipids.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Several of the above and numerous additional therapeutic agentsappropriate for the practice of the present invention are disclosed inU.S. Pat. No. 5,733,925, which is incorporated herein by reference.Therapeutic agents disclosed in this patent include the following:“Cytostatic agents” (i.e., agents that prevent or delay cell division inproliferating cells, for example, by inhibiting replication of DNA or byinhibiting spindle fiber formation). Representative examples ofcytostatic agents include modified toxins, methotrexate, adriamycin,radionuclides (e.g., such as disclosed in Fritzberg et al., U.S. Pat.No. 4,897,255), protein kinase inhibitors, including staurosporin, aprotein kinase C inhibitor of the following formula:

as well as diindoloalkaloids having one of the following generalstructures:

as well as stimulators of the production or activation of TGF-beta,including Tamoxifen and derivatives of functional equivalents (e.g.,plasmin, heparin, compounds capable of reducing the level orinactivating the lipoprotein Lp(a) or the glycoproteinapolipoprotein(a)) thereof, TGF-beta or functional equivalents,derivatives or analogs thereof, suramin, nitric oxide releasingcompounds (e.g., nitroglycerin) or analogs or functional equivalentsthereof, paclitaxel or analogs thereof (e.g., taxotere), inhibitors ofspecific enzymes (such as the nuclear enzyme DNA topoisomerase II andDNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxidedismutase inhibitors, terminal deoxynucleotidyl-transferase, reversetranscriptase, antisense oligonucleotides that suppress smooth musclecell proliferation and the like.

Other examples of “cytostatic agents” include peptidic or mimeticinhibitors (i.e., antagonists, agonists, or competitive ornon-competitive inhibitors) of cellular factors that may (e.g., in thepresence of extracellular matrix) trigger proliferation of smooth musclecells or pericytes: e.g., cytokines (e.g., interleukins such as IL-1),growth factors (e.g., PDGF, TGF-alpha or -beta, tumor necrosis factor,smooth muscle- and endothelial-derived growth factors, i.e., endothelin,FGF), homing receptors (e.g., for platelets or leukocytes), andextracellular matrix receptors (e.g., integrins). Representativeexamples of useful therapeutic agents in this category of cytostaticagents addressing smooth muscle proliferation include: subfragments ofheparin, triazolopyrimidine (trapidil; a PDGF antagonist), lovastatin,and prostaglandins E1 or I2.

Agents that inhibit the intracellular increase in cell volume (i.e., thetissue volume occupied by a cell) such as cytoskeletal inhibitors ormetabolic inhibitors. Representative examples of cytoskeletal inhibitorsinclude colchicine, vinblastin, cytochalasins, paclitaxel and the like,which act on microtubule and microfilament networks within a cell.Representative examples of metabolic inhibitors include staurosporin,trichothecenes, and modified diphtheria and ricin toxins, Pseudomonasexotoxin and the like. Trichothecenes include simple trichothecenes(i.e., those that have only a central sesquiterpenoid structure) andmacrocyclic trichothecenes (i.e., those that have an additionalmacrocyclic ring), e.g., a verrucarins or roridins, including VerrucarinA, Verrucarin B, Verrucarin J (Satratoxin C), Roridin A, Roridin C,Roridin D, Roridin E (Satratoxin D), Roridin H.

Agents acting as an inhibitor that blocks cellular protein synthesisand/or secretion or organization of extracellular matrix (i.e., an“anti-matrix agent”). Representative examples of “anti-matrix agents”include inhibitors (i.e., agonists and antagonists and competitive andnon-competitive inhibitors) of matrix synthesis, secretion and assembly,organizational cross-linking (e.g., transglutaminases cross-linkingcollagen), and matrix remodeling (e.g., following wound healing). Arepresentative example of a useful therapeutic agent in this category ofanti-matrix agents is colchicine, an inhibitor of secretion ofextracellular matrix. Another example is tamoxifen for which evidenceexists regarding its capability to organize and/or stabilize as well asdiminish smooth muscle cell proliferation following angioplasty. Theorganization or stabilization may stem from the blockage of vascularsmooth muscle cell maturation in to a pathologically proliferating form.

Agents that are cytotoxic to cells, particularly cancer cells. Preferredagents are Roridin A, Pseudomonas exotoxin and the like or analogs orfunctional equivalents thereof. A plethora of such therapeutic agents,including radioisotopes and the like, have been identified and are knownin the art. In addition, protocols for the identification of cytotoxicmoieties are known and employed routinely in the art.

A number of the above therapeutic agents and several others have alsobeen identified as candidates for vascular treatment regimens, forexample, as agents targeting restenosis. Such agents are appropriate forthe practice of the present invention and include one or more of thefollowing:

-   -   Calcium-channel blockers including:        -   Benzothiazapines such as diltiazem and clentiazem        -   Dihydropyridines such as nifedipine, amlodipine and            nicardapine        -   Phenylalkylamines such as verapamil    -   Serotonin pathway modulators including:        -   5-HT antagonists such as ketanserin and naftidrofuryl        -   5-HT uptake inhibitors such as fluoxetine    -   Cyclic nucleotide pathway agents including:        -   Phosphodiesterase inhibitors such as cilostazole and            dipyridamole        -   Adenylate/Guanylate cyclase stimulants such as forskolin        -   Adenosine analogs    -   Catecholamine modulators including:        -   α-antagonists such as prazosin and bunazosine        -   β-antagonists such as propranolol        -   α/β-antagonists such as labetalol and carvedilol    -   Endothelin receptor antagonists    -   Nitric oxide donors/releasing molecules including:        -   Organic nitrates/nitrites such as nitroglycerin, isosorbide            dinitrate and amyl nitrite        -   Inorganic nitroso compounds such as sodium nitroprusside        -   Sydnonimines such as molsidomine and linsidomine        -   Nonoates such as diazenium diolates and NO adducts of            alkanediamines        -   S-nitroso compounds including low molecular weight compounds            (e.g., S-nitroso derivatives of captopril, glutathione and            N-acetyl penicillamine), high molecular weight compounds            (e.g., S-nitroso derivatives of proteins, peptides,            oligosaccharides, polysaccharides, synthetic            polymers/oligomers and natural polymers/oligomers)        -   C-nitroso-, O-nitroso- and N-nitroso-compounds L-arginine    -   ACE inhibitors such as cilazapril, fosinopril and enalapril    -   ATII-receptor antagonists such as saralasin and losartin    -   Platelet adhesion inhibitors such as albumin and polyethylene        oxide    -   Platelet aggregation inhibitors including:        -   Aspirin and thienopyridine (ticlopidine, clopidogrel)        -   GP IIb/IIIa inhibitors such as abciximab, epitifibatide and            tirofiban    -   Coagulation pathway modulators including:        -   Heparinoids such as heparin, low molecular weight heparin,            dextran sulfate and β-cyclodextrin tetradecasulfate        -   Thrombin inhibitors such as hirudin, hirulog,            PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and            argatroban        -   FXa inhibitors such as antistatin and TAP (tick            anticoagulant peptide)        -   Vitamin K inhibitors such as warfarin        -   Activated protein C    -   Cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,        flurbiprofen, indomethacin and sulfinpyrazone    -   Natural and synthetic corticosteroids such as dexamethasone,        prednisolone, methprednisolone and hydrocortisone    -   Lipoxygenase pathway inhibitors such as nordihydroguairetic acid        and caffeic acid    -   Leukotriene receptor antagonists    -   Antagonists of E- and P-selectins    -   Inhibitors of VCAM-1 and ICAM-1 interactions    -   Prostaglandins and analogs thereof including:        -   Prostaglandins such as PGE1 and PGI2        -   Prostacyclin analogs such as ciprostene, epoprostenol,            carbacyclin, iloprost and beraprost    -   Macrophage activation preventers including bisphosphonates    -   HMG-CoA reductase inhibitors such as lovastatin, pravastatin,        fluvastatin, simvastatin and cerivastatin    -   Fish oils and omega-3-fatty acids    -   Free-radical scavengers/antioxidants such as probucol, vitamins        C and E, ebselen, trans-retinoic acid and SOD mimics    -   Agents affecting various growth factors including:    -   FGF pathway agents such as bFGF antibodies and chimeric fusion        proteins    -   PDGF receptor antagonists such as trapidil    -   IGF pathway agents including somatostatin analogs such as        angiopeptin and ocreotide    -   TGF-β pathway agents such as polyanionic agents (heparin,        fucoidin), decorin, and TGF-β antibodies    -   EGF pathway agents such as EGF antibodies, receptor antagonists        and chimeric fusion proteins    -   TNF-α pathway agents such as thalidomide and analogs thereof.    -   Thromboxane A2 (TXA2) pathway modulators such as sulotroban,        vapiprost, dazoxiben and ridogrel    -   Protein tyrosine kinase inhibitors such as tyrphostin, genistein        and quinoxaline derivatives    -   MMP pathway inhibitors such as marimastat, ilomastat and        metastat    -   Cell motility inhibitors such as cytochalasin B    -   Antiproliferative/antineoplastic agents including:        -   Antimetabolites such as purine analogs (6-mercaptopurine),            pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and            methotrexate        -   Nitrogen mustards, alkyl sulfonates, ethylenimines,            antibiotics (e.g., daunorubicin, doxorubicin), nitrosoureas            and cisplatin        -   Agents affecting microtubule dynamics (e.g., vinblastine,            vincristine, colchicine, paclitaxel and epothilone)        -   Caspase activators        -   Proteasome inhibitors        -   Angiogenesis inhibitors (e.g., endostatin, angiostatin and            squalamine)        -   Rapamycin, cerivastatin, flavopiridol and suramin    -   Matrix deposition/organization pathway inhibitors such as        halofuginone or other quinazolinone derivatives and tranilast    -   Endothelialization facilitators such as VEGF and RGD peptide    -   Blood rheology modulators such as pentoxifylline.

In some embodiments, particle 100 can include a combination of any ofthe above therapeutic agents.

Therapeutic agents are described, for example, in co-pending PublishedPatent Application No. US 2004/0076582 A1, published on Apr. 22, 2004,and entitled “Agent Delivery Particle”, which is incorporated herein byreference, and in Pinchuk et al., U.S. Pat. No. 6,545,097, which isincorporated herein by reference.

Particles 150 can be formed using any of various systems and techniques,such as emulsion polymerization and/or droplet polymerizationtechniques. Examples of such systems and techniques are described, forexample, in co-pending Published Patent Application No. US 2003/0185896A1, published Oct. 2, 2003, and entitled “Embolization,” and inco-pending Published Patent Application No. US 2004/0096662 A1,published May 20, 2004, and entitled “Embolization,” each of which isincorporated herein by reference.

While certain embodiments have been described, other embodiments arealso possible.

As an example, particles 150 can include (e.g., encapsulate) diagnosticagent(s) such as a radiopaque material, an MRI-visible material, aferromagnetic material, and/or an ultrasound contrast agent. Forexample, particle 150 can encapsulate a ferromagnetic material so thatthe position of the particle in a lumen can be manipulated with amagnetic field. The magnetic field can be created outside the subject orinside the subject (e.g., via a magnetic catheter). Particles containingdiagnostic agents are described in U.S. patent application Ser. No.10/651,475, filed on Aug. 29, 2003, and entitled “Embolization”, andmagnetic devices are described in U.S. patent application Ser. No.10/108,874, filed on Mar. 29, 2002, and entitled “Magnetically EnhancedInjection Catheter,” both of which are incorporated herein by reference.

As an additional example, while embodiments have been described in whichprotective layer 145 is formed of particles, in some embodiments,protective layer 145 is formed of one or more liquid polymers. Examplesof polymers from which a liquid polymer can be formed include thosenoted above. In some embodiments, a liquid polymer can be a carrierfluid for particles. A liquid polymer can be disposed between twoportions of tissue using the methods described above (e.g., via aneedle, a syringe, or a catheter).

As another example, in some embodiments, protective layer 145 is formedof one or more gels. A gel can be formed of, for example, one or morepolymers. Examples of polymers include those noted above. A gel can bedisposed between two portions of tissue using the methods describedabove (e.g., via a needle, a syringe, or a catheter).

As a further example, in some embodiments, protective layer 145 isformed from one or more gases. Examples of gases include helium, neon,argon, krypton, xenon, air, nitrogen, and carbon dioxide. In someembodiments, a gas can be a carrier fluid for particles. A gas can bedisposed between two portions of tissue using the methods describedabove (e.g., via a needle, a syringe, or a catheter).

As an additional example, in some embodiments, protective layer 145 isformed from one or more foams. A foam can be formed of, for example, oneor more polymers. Examples of polymers include those noted above. A foamcan be disposed between two portions of tissue using the methodsdescribed above (e.g., via a needle, a syringe, or a catheter).

As another example, protective layer 145 can be formed of deionizedwater and/or a buffered saline solution. The buffered saline solution,for example, can include a composition of saline solution and any ofvarious buffers, such as phosphate. In certain embodiments, thedeionized water can similarly include a buffer material, such asphosphate. In some embodiments, the deionized water and/or the bufferedsaline solution can provide an electrical resistance of about 175 kohmsor greater (e.g., about 200 kohms or greater, about 225 kohms orgreater, about 250 kohms or greater, about 275 kohms or greater, about300 kohms or greater, about 325 kohms or greater, about 350 kohms orgreater). As used herein, the electrical resistance is tested using ASTMD257-99.

As a further example, in certain embodiments, protective layer 145 canbe formed of a combination of one or more of the following: deionizedwater; a buffered saline solution; particles; liquid polymers; gels;gases and/or foams.

As another example, while certain forms of energy have been described,other forms of energy can be used to treat medical conditions. Examplesof forms of energy that can be used include microwave energy, ultrasonicenergy, laser energy, and/or heat. Similarly, the unhealthy tissue canbe cooled. The energy can be administered to the unhealthy tissue usingany of various techniques. For example, a probe can be inserted into theunhealthy tissue and activated to release one or more types of energy.

In some embodiments particles including a relatively conductive material(e.g., a ferromagnetic material) can be disposed within the tissue ofthe subject to enhance the effects of the energy (e.g., RF energy)transmitted to unhealthy tissue 140. In certain embodiments in whichparticles including a ferromagnetic material have been disposed withinthe tissue, a magnetic field can be applied to the particles to affectthe extent of conductivity. The magnetic field can be varied to adjustthe conductivity of the particles (and, therefore, to adjust the extentof heating and ablation caused by the transmitted energy). In someembodiments, the particles can be used in an agitation ablation process.In such a process, a magnetic field can be used to agitate theparticles, such that the particles heat and/or physically deform thesurrounding tissue, thereby ablating the surrounding tissue. These andother tissue treatment techniques are described in U.S. Pub. Pat. App.No. US-2004-0101564-A1, which is incorporated herein by reference.

As an additional example, while embodiments have been described in whichunhealthy liver tissue is treated, other types of unhealthy tissue canalso be treated. Examples of other types of tissue that can be treatedinclude bodily vessel tissue, bone tissue, brain tissue, breast tissue,kidney tissue, liver tissue, lung tissue, ovary tissue, prostate tissue,skin tissue, and thyroid tissue.

As a further example, in some embodiments, energy can be used to treathealthy tissue. In some embodiments, for example, the healthy tissue isundesired tissue. For example, energy can be used to treat (e.g.,remove) various types of malformed tissue, such as tissue resulting inwebbed fingers and/or toes. As a further example, energy can be used totreat various types of malfunctioning tissue. In embodiments in whichhealthy tissue is treated with energy, it may be desired, for example,to preserve adjacent regions of healthy tissue. Thus, protective layer145 can be disposed between two regions of healthy tissue.

The medical treatments described herein can similarly be used to treatvarious other types of medical conditions. For example, in someembodiments, regions of brain tissue may be treated (e.g., destroyed)with electrical stimulation to treat epilepsy. Similarly, regions ofnerve tissue may be treated (e.g., destroyed) to treat chronic pain. Incertain embodiments, regions of bodily vessel tissue can be treated toocclude the vessel. This can be beneficial, for example, in treatingfibroids (e.g., uterine fibroids), varicose veins, alterior venousmalformations, and certain forms of trauma.

Other embodiments are in the claims.

1. A method, comprising: separating a first portion of tissue of asubject from a second portion of tissue of the subject so that there isa space between the first and second portions of tissue; disposing amaterial between the first and second portions of tissue; and exposingthe first portion of tissue to energy to treat the first portion oftissue, wherein: the material is selected from at least one member ofthe group consisting of deionized water, a buffered saline solution,liquid polymers, gels, particles, foams and gases; and the secondportion of tissue is substantially unexposed to the energy while thefirst portion of tissue is exposed to the energy.
 2. The method of claim1, wherein the energy comprises at least one member selected from thegroup consisting of RF energy, microwave energy, ultrasonic energy,laser energy, and heat.
 3. The method of claim 1, wherein exposing thefirst portion of tissue to energy comprises cooling the first portion oftissue.
 4. The method of claim 1, wherein the first portion of tissuecomprises an unhealthy tissue.
 5. The method of claim 4, wherein thefirst portion of tissue comprises cancerous tissue.
 6. The method ofclaim 4, wherein the second portion of tissue comprises a healthytissue.
 7. The method of claim 1, wherein the first portion of tissuecomprises at least one member of the group consisting of bodily vesseltissue, bladder tissue, bone tissue, brain tissue, breast tissue,bronchi tissue, diaphragm tissue, esophagus tissue, gall bladder tissue,heart tissue, intestine tissue, kidney tissue, larynx tissue, livertissue, lung tissue, lymph vessel tissue, lymph node tissue, nervetissue, ovary tissue, pancreas tissue, prostate tissue, skin tissue,stomach tissue, thyroid tissue, trachea tissue, urethra tissue, uretertissue, uterus tissue, and vertebral disc tissue.
 8. The method of claim1, wherein the second portion of tissue comprises at least one member ofthe group consisting of bodily vessel tissue, bladder tissue, bonetissue, brain tissue, breast tissue, bronchi tissue, diaphragm tissue,esophagus tissue, gall bladder tissue, heart tissue, intestine tissue,kidney tissue, larynx tissue, liver tissue, lung tissue, lymph vesseltissue, lymph node tissue, nerve tissue, ovary tissue, pancreas tissue,prostate tissue, skin tissue, stomach tissue, and thyroid tissue,trachea tissue, urethra tissue, ureter tissue, uterus tissue, andvertebral disc tissue.
 9. The method of claim 1, wherein the firstportion of tissue is the same type of tissue as the second portion oftissue.
 10. The method of claim 1, wherein the material comprises aliquid polymer.
 11. The method of claim 10, wherein the liquid polymercomprises at least one member selected from the group consisting ofpolyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinylsulfonates, carboxymethyl celluloses, hydroxyethyl celluloses,substituted celluloses, polyacrylamides, polyethylene glycols,polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co- glycolic) acids, polypropylene, polytetrafluorethylene,polyethyleneterephthalate, polycarbonate, polyphenyleneoxide,polysulfone, polyhydantoine, polyamide-imide, polyimide, cellulosetriacetate, and cellulose acetate butyrate.
 12. The method of claim 1,wherein the material comprises a gel.
 13. The method of claim 12,wherein the gel comprises at least one member selected from the groupconsisting of polyvinyl alcohols, polyacrylic acids, polymethacrylicacids, poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethylcelluloses, substituted celluloses, polyacrylamides, polyethyleneglycols, polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co- glycolic) acids, polypropylene, polytetrafluorethylene,polyethyleneterephthalate, polycarbonate, polyphenyleneoxide,polysulfone, polyhydantoine, polyamide-imide, polyimide, cellulosetriacetate, and cellulose acetate butyrate.
 14. The method of claim 1,wherein the material comprises particles.
 15. The method of claim 14,wherein the particles have a size of at most about 10,000 microns. 16.The method of claim 14, wherein the particles comprise at least onematerial selected from the group consisting of polyvinyl alcohols,polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,carboxymethyl celluloses, hydroxyethyl celluloses, substitutedcelluloses, polyacrylamides, polyethylene glycols, polyamides,polyureas, polyurethanes, polyesters, polyethers, polystyrenes,polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co- glycolic) acids, polypropylene, polytetrafluorethylene,polyethyleneterephthalate, polycarbonate, polyphenyleneoxide,polysulfone, polyhydantoine, polyamide-imide, polyimide, cellulosetriacetate, and cellulose acetate butyrate.
 17. The method of claim 1,wherein the particles comprise a material having a dielectric constantof at least about 2.1.
 18. The method of claim 1, wherein the particlescomprise a material having a dielectric strength of at least about 100Kv/mm.
 19. The method of claim 1, wherein the material comprises a foam.20. The method of claim 19, wherein the foam comprises at least onemember selected from the group consisting of polyvinyl alcohols,polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,carboxymethyl celluloses, hydroxyethyl celluloses, substitutedcelluloses, polyacrylamides, polyethylene glycols, polyamides,polyureas, polyurethanes, polyesters, polyethers, polystyrenes,polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co- glycolic) acids, polypropylene, polytetrafluorethylene,polyethyleneterephthalate, polycarbonate, polyphenyleneoxide,polysulfone, polyhydantoine, polyamide-imide, polyimide, cellulosetriacetate, and cellulose acetate butyrate.
 21. The method of claim 1,wherein the material comprises a gas.
 22. The method of claim 1, whereinthe material comprises deionized water.
 23. The method of claim 1,wherein the material comprises a buffered saline solution.
 24. Themethod of claim 1, wherein the material comprises at least one memberselected from the group consisting of water soluble polysaccharides andionically cross- linkable polymers.
 25. The method of claim 1, whereinthe material comprises a ceramic material.
 26. The method of claim 1,wherein the material is capable of undergoing an endothermic reaction.27. The method of claim 1, wherein the space between the first andsecond portions of tissue is at most about five centimeters.
 28. Amethod, comprising: separating a first portion of tissue of a subjectfrom a second portion of tissue of the subject so that there is a spacebetween the first and second portions of tissue; disposing a materialbetween the first and second portions of tissue; and exposing the firstportion of tissue to energy to treat the first portion of tissue,wherein: the material is selected from at least one member of the groupconsisting of deionized water, a buffered saline solution, liquidpolymers, gels, particles, foams and gases; and the second portion oftissue is substantially unexposed to the energy while the first portionof tissue is exposed to the energy, and the space between the first andsecond portions of tissue is at most about five centimeters.
 29. Themethod of claim 28, wherein the energy comprises at least one memberselected from the group consisting of RF energy, microwave energy,ultrasonic energy, laser energy, and heat.
 30. The method of claim 28,wherein exposing the first portion of tissue to energy comprises coolingthe first portion of tissue.
 31. The method of claim 28, wherein thematerial comprises a liquid polymer.
 32. The method of claim 28, whereinthe material comprises a gel.
 33. The method of claim 28, wherein thematerial comprises particles.
 34. The method of claim 33, wherein theparticles have a size of at most about 10,000 microns.
 35. The method ofclaim 28, wherein the material comprises a foam.
 36. The method of claim28, wherein the material comprises a gas.
 37. The method of claim 28,wherein the material comprises deionized water.
 38. The method of claim28, wherein the material comprises a buffered saline solution.
 39. Themethod of claim 28, wherein the material comprises at least one memberselected from the group consisting of water soluble polysaccharides andionically cross-linkable polymers.
 40. The method of claim 28, whereinthe material comprises a ceramic material.
 41. The method of claim 28,wherein the material is capable of undergoing an endothermic reaction.